Homeostatic signaling systems are believed to interface with the mechanisms of neural plasticity to stabilize activity throughout the vertebrate and invertebrate nervous systems. At present, the molecular mechanisms responsible for the homeostatic control of neural function remain largely unknown. The Davis laboratory has identified a conserved form of homeostatic signaling that controls synaptic transmission at the Drosophila neuromuscular junction (NMJ). In a forward genetic screen for mutations that block synaptic homeostasis, we identified comatose, which encodes the Drosophila homolog of the N-ethylmaleimide-sensitive fusion protein (NSF). Although NSF is known to be important for synaptic transmission, it remains to be determined whether and how NSF functions in vesicle fusion, endocytosis, or elsewhere in the vesicle cycle. Intriguingly, comatose mutations show a strong genetic interaction with mutations in the CaV2.1 presynaptic calcium channel, which has previously been implicated in the mechanisms of synaptic homeostasis. Here I propose a detailed characterization of Comatose function during synaptic transmission and during homeostatic plasticity. By completing the proposed experiments I will define the function of Comatose at the synapse. I will simultaneously explore the molecular cascade underlying homeostatic plasticity and elucidate the role of Comatose as a molecular link between vesicle recycling and calcium channel activity. PUBLIC HEALTH RELEVANCE: Neural systems actively work to maintain a constant output in the face of changing inputs: too little activity destroys brain cells'ability to communicate;too much leads to over-excitation and epilepsy or migraines, diseases which affect over 10% of the population. A few genes have been previously shown to be involved in the cellular processes controlling this stability, but how they work together remains unknown. We plan to characterize a gene which exists in flies and in humans, and which appears to be the link connecting these disparate cellular signals;this characterization will open the door to many new treatments for diseases of neuronal over-activity.